ETIOLOGY, PATHOPHYSIOLOGY AND

UPDATES ON THE DIETARY MANAGEMENT

FOR PATIENTS WITH LUNG CANCER

WINDFIED
WINDFIED L.
L. TAN
TAN MD.,
MD., FPCP,
FPCP, FPCCP
FPCCP
 OBJECTIVES

 To discuss both proven and suspected causes of lung

cancer

 To discuss the basic pathophysiology of lung cancer

 To discuss updates in the dietary management of lung

cancer patient
CANCER STATISTICS (USA)

Jemal A et al. Ca Cancer J Clinic 2004;54:8-29

 LEADING CANCER SITES,AGE STANDARDIZED
RATES/100,000p, ALL AGES (R.P)
Cancer sites 1980-82 1983-87 1988-92 1993-95
M F M F M F M F
Lung 42 11 47 15 64 19 65 19
Breast 0.7 40 0.7 44 0.8 43 0.8 43
Liver 20 7.3 20 8.0 26 9.0 26 9
Cervix --- 20 --- 23 --- 27 --- 27

Stomach 12 8 11 8 12 8 12 8
Colon 7 6 8 8 9 8 9 8
Prostate 13 --- 15 --- 20 --- 20 ---
Oral cavity 5 6 6 7 9 8 8 8
Rectum 6 3 2 6 8 6 8 6

Ludovice ZA et al. Phil Health Statistics 1991 Health Intelligence Service, DOH 1995
2005 Philippine Cancer Facts and Estimates
WHO HISTOLOGIC CLASSIFICATION (LUNG CANCER)

Dysplasia/carcinoma in situ
Squamous cell ca……………………............. 30. 0%
Adenocarcinoma ………………………………. 30.7%
Large cell ca ………………………………………. 9.4%
Adenosquamous ca…………………………….. 1.5%
Small cell ca ……………………………………….. 18.2%
Carcinoid …………………………………………… 1.0%
Bronchial gland carcinoma …………………… <0.1%
All others and unspecified carcinomas ….. 11%

Travis et al. Cancer 1995

 WHO HISTOLOGIC CLASSIFICATION (LUNG CANCER)

Dysplasia/carcinoma in situ

Squamous cell ca (30%)

Adenocarcinoma (30.7%) NON-SMALL CELL CA
Large cell ca (9.4%) 71.6%
Adenosquamous ca (1.5%)

Small cell ca 18.2%

Carcinoid (1.0%)
Bronchial gland carcinoma (<0.1%)
All others and unspecified carcinomas(11%)

Travis et al. Cancer 1995

 LUNG CANCER HISTOPATHOLOGY

ADENOCARCINOMA SMALL CELL CARCINOMA

 IMAGING IN LUNG CANCER

CHEST X-RAY CHEST CT SCAN

 THE ETIOLOGY OF LUNG CANCER

• SMOKING

• DIET

• ASBESTOS

• RADIATION

• AIR POLLUTION

• HOST FACTORS
THE LEADING CAUSE OF LUNG CANCER
 SMOKING AND LUNG CANCER

• Smokers risk of lung cancer (20-100 fold)

• Passive smoking causally increased risk for lung

cancer (1.5-fold)

• Rate of occurrence lags smoking rates by 20 years

• Best mode of prevention is smoking cessation

NIH and NCI: Smoking and Cigars:Health effects and Trends.

Tobacco Control Monograph,US Dept of Health and Services, 1998
 Lung Cancer Mortality Rate(per 100,000) among men and women
60-69 Years of Age with Comparable Smoking Levels in the
American Cancer Prevention Study(CPS-II)

Group never-smoker smoked 20 cig/day smoked 40 cig/day

30 years 40 years 30 years 40 years
(Duration of smoking)

Men 11.9 224 487 573 606

Women 9.8 201 264 258 552

Thun MJ. Et al. National Cancer Institute 1997

 Risk of Lung Cancer among Ex-smokers Relative to
Never Smokers According to Length of Time since
Smoking Cessation

Years since Cigarette Smoked per Day

Smoked
1-9 10-20 21-39 >40 Total

<5 7.6 * 12.5 20.6 26.9 16.1

5-9 3.6 5.1 11.5 13.6 7.8
10-19 2.2 4.3 6.8 7.8 5.1
20-29 1.7 3.3 3.4 5.9 3.3
30-39 0.5 2.1 2.8 4.5 2.0
>40 1.1 1.6 1.8 2.3 1.5

* Relative risk compared to referent category of never smokers (=1.0).

Hrubert MZ. Et al Natl Cancer Inst 1997
The effect of smoking cessation intervention on 14.5
year mortality: A Randomized Clinical Trial

Nicholas R et al. Lung Health Study Group; Annals Intern Med 2005;142;233-239
The effect of smoking cessation intervention on 14.5 year
mortality: A Randomized Clinical Trial
Nicholas R et al. Lung Health Study Group; Annals Intern Med 2005;142;233-239

All-cause 14.5 year survival

SMOKING CESSATION CLINIC
 DIET AND LUNG CANCER

• Fruits and vegetables are the major source of

micronutrients (ex. ß-carotene)

• Past studies showed lower risk of lung cancer in

individuals with higher consumption of fruits and
vegetables

• Latest randomized trials with high doses of ß-

carotene did not showed protective effects (ATBC
trial)

Newhouser ML. et al. Cancer Epi Biomarkers Prev 2003

Omenn GS et al. Natl. Cancer Inst 1996
The Effect of Vitamin E and Beta Carotene on the Incidence of
Lung Cancer (ATBC) Trial

Omenn GS. J Natl Cancer Inst 1996

 ENVIRONMENT AND LUNG CANCER

1. OCCUPATIONAL EXPOSURES

• ASBESTOS
• RADIATION

2. AIR POLLUTION

• ATMOSPHERIC
• INDOOR
 ASBESTOS AND LUNG CANCER

• Asbestos textile workers has a 10-fold increased risk

(UK); Insulation workers has a 7-fold increased in risk
(US)

• Peak incidence occurred 30-35 years after exposure

• Asbestos and smoking act synergistically ( 50-fold

increased risk)

Brown K. Br J ind Med 1986 Doll R. et al. Br J ind Med 1995

Latency of Asbestos Disease among Insulation Workers

# of
Lung
Cancer
cases

Years of Asbestos Exposure

Selikoff et al. JAMA 1964;188:22-26

 Relationship between Asbestos and Cigarette
Exposure on Risk of Lung Cancer Mortality

Mortality Additive Multiplicative

rate model model

Asbestos Asbestos Asbestos

Exposed Exposed Exposed

Smoking NO YES NO YES NO YES

NO 11 58 0 47 1 5

YES 122 601 111 59 11 53

Hammond et al. Ann NY Acad Sci 1979;330,473-490

 RADIATION AND LUNG CANCER

1. HIGH-LINEAR ENERGY TRANSFER

• NEUTRONS
• RADONS

• LOW-LINEAR ENERGY TRANSFER

• GAMMA RAYS
• X-RAYS
 RADIATION AND LUNG CANCER

HIGH-LET RADIATION (RADON)

• EMITS ALPHA PARTICLE

• UNDERGROUND MINERS

• INDOOR POLLUTANT

Lubin JH et al. J Natl. Cancer Institute 1995

 RADIATION AND LUNG CANCER

LOW-LET RADIATION

• ATOMIC BOMB SURVIVORS

• OCCUPATIONAL GROUPS

Shimizu et al JAMA 1990 Gilbert et al. Radiol Res 1999 Davis FG et al Cancer Res 1989
 AIR POLLUTION AND LUNG CANCER

ATMOSPHERIC

• PAH AND METALS (arsenic, nickel, chromium), sulfate

• LONG-TERM TRAFFIC EXPOSURE; PROXIMITY OF RESIDENCE TO

SOURCE

• LUNG CA MORTALITY ASSOCIATED WITH HIGHEST PARTICULATE

CONCENTRATION ( 6 U.S cities study, CPS-II)

Doll R. Peto R. J Natl Cancer Inst 1981 Friberg et al. Envim Health Prog 1978 Dockery DW. NEJM 1995
Beelen et al: long term exposure to traffic-related air pollution and lung ca risk, Epidemiology,2008,
 AIR POLLUTION AND LUNG CANCER

IN-DOOR

• TOBACCO SMOKE, BUILDING MATERIALS, SOIL GASES

HOUSEHOLD PRODUCTS, COOKING AND HEATING

• PASSIVE SMOKE, RADON( developed countries)

• SMOKY COAL FOR COOKING ( xuan wei, china)

Nat Res Coun,Nat Academy Presss 1988 Mumford JL. China Science 1987
 HOST FACTORS AND LUNG CANCER

• GENETIC SUSCEPTIBILITY

• PRESENCE OF HIV

• PRESENCE OF ACQUIRED LUNG DISEASE

• GENDER
GENETICS SUSCEPTIBILITY AND LUNG CANCER

GENETICS

• SUSCEPTIBILITY FACTOR

• HYPOTHESIS: INHERENTLY DETERMINED

• MOLECULAR EPIDEMIOLOGY

Hecht et al. J Natl Cancer Inst 1999

 GENETICS AND LUNG CANCER

DEFECTS IN HUMAN GENE

o CARCINOGEN METABOLISM AND ACTIVATION

o DNA REPAIR

o CELL CYCLE CONTROL

o APOPTOSIS
 SPECIFIC GENETIC VARIANTS IN CARCINOGEN METABOLISM
LEADING TO DEVELOPMENT OF LUNG CANCER

Carcinogen Metabolic Activation Persistence

(Cigarette smoke) (CYPIA)

PAH,NNK, Mutations in…

Nicotine DNA
And other RAS,MYC,P53,
Addiction Adducts
Carcinogens P16,RB,FHIT &
Other critical
genes
Metabolic Detoxification Repair
(GTT) (XPAi,XPD)

Apoptosis
Lung Cancer
Excretion Normal DNA

Hecht SS.J Natl Cancer Inst 1999

 HOST FACTORS AND LUNG CANCER

PRESENCE OF HIV INFECTION

• INCREASED RISK

• SMOKING AND HIV IS SYNERGISTIC

• HIV AS VIRAL CARCINOGEN

• DEFECTIVE IMMUNE SURVEILLANCE

• LUNG SCAR FORMATION

Bower M,Powles T et al:HIV-related lung cancer in the era of HAART.AIDS,2003

Shiels MS et al: Meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals,2009
 HOST FACTORS AND LUNG CANCER

PRESENCE OF ACQUIRRED LUNG DISEASE

• COPD

• PNEUMOCONIOSIS (silicosis)

• POST-INFLAMMATORY SCARRING

SinDD et al: impact of cancers and CVS disease in COPD,2008

Ng TP et al: Silica and lung cancer: a continuing controversy.Ann Acad Med Singapore,1994
MOLECULAR PATHOGENESIS OF LUNG CANCER

• Activation of Dominant Oncogenes

• Inactivation of Tumor-Suppressor Genes

• Autocrine Growth Factors

• Inherited Predisposition to lung cancer

MOLECULAR PATHOGENESIS OF LUNG CANCER

ACTIVATION OF DOMINANT ONCOGENES

• Point mutation in KRAS gene in adenocarcinoma

• Point mutation in TK domain of EGFR gene in adenocarcinoma in

nonsmokers

• Loss of transcriptional control on myc gene in small cell lung ca

• Overexpression of bcl-2, ERBB3,telomerase gene

Sato M et al: Molecular genetics of lung cancerand translation to the clinic. J.Thoracic Oncol,2007
 MOLECULAR PATHOGENESIS OF LUNG CANCER

INACTIVATION OF TUMOR-SUPPRESSOR GENE

• Loss of growth regulatory function in

p53, RB,RASSF1A, SEMA3B,
SEMA3F,FUS1,p16,LKB1,RARß,FHIT

Sato M et al: Molecular genetics of lung cancerand translation to the clinic. J.Thoracic Oncol,2007
MOLECULAR PATHOGENESIS OF LUNG CANCER

AUTOCRINE GROWTH FACTORS

• Lung cancer cells expresses nicotinic acetylcholine receptors

• Nicotine in cigarette smoke activates signaling pathways in

normal and tumor cells

• Nicotine itself is considered a tumor promoter and a mutagen

Sato M et al: Molecular genetics of lung cancerand translation to the clinic. J.Thoracic Oncol,2007
MOLECULAR PATHOGENESIS OF LUNG CANCER

• a person can inherit mutations in p53 gene(Li-Fraumeni

syndrome) and may develop lung cancer

• 1st degree relatives of lung cancer have 2-3-fold excess risk of

lung cancer

• Polymorphisms of the P450 enzyme system are associated

with development of lung cancer
 NUTRITION AND PULMONARY DISEASE

• EFFECTS OF NUTRITION ON PULMONARY FUNCTION

• NUTRIENT IMPACT ON PULMONARY FUNCTION

• MODE OF NUTRITION IN LUNG CANCER PATIENTS

 NUTRITION AND PULMONARY DISEASE

POOR NUTRITIONAL STATUS

• Impairs structural & functional components

• Reduced endurance of respiratory muscles
• Reduced ventilatory drive and inefficient gas exchange
• Hypoalbuminemia may lead to pulmonary edema
• Decreased FRC
• Impaired immune response

Silver Spring MD et al: American Society of Parenteral and Enteral Nutrition, 2007
Benotti PN et al: Metabolic and Nutritional aspect of weaning from mechanical ventilator, Crit care med, 1989
Seiidner D et al: Nutrition support in liver, pulmonary and renal disease,Nutrition support,Theory and therapeutics, 1997
 NUTRITION AND PULMONARY DISEASE

NUTRIENT IMPACT ON PULMONARY FUNCTION

• CHO in excess of 5mg/kg/min increases CO2 production

• Fat for CHO calories substitution may lower R/Q

• CHON requirement usually is increased at 1.5-2.0g/kg/day

Kuo CD et al: The effects of high-fats and high-CHO diet loads on gas exchange and ventilation on COPD patients and normal subjects,Chest,1995.
Jih KS et al: Hypercapneic respiratory acidosisprecipitated by hypercaloric CHO infusion in resolving septic ARDS,Chin Med J,1996.
Grant JP et al: Nutrition care of patients with acute and chronic respiratory failure, ,Nutri Clin Pract, 1994
MULTIMODALITY TREATMENT FOR LUNG CANCER

SURGERY ± CHEMOTHERAPY ± RADIATION ± BSC

 CACHEXIA

Cancer

cytokines Proteolyis Lipid

Inducing Factor Mobilizing Factor

Physical obstruction

Loss of appetite Protein Loss Fat Loss No Intake

Very thin; progressive weight loss not corrected by increased intake

 CANCER AND MALNUTRITION

Energy Expenditure in Cancer Patients

23.5
25 22
20.5
18
REE (kcal/kg/day)

20
15
cancer
10 control
5
0
wt_stable wt_losing

Hyltander et al, 1991

WEIGHT LOSS IN CANCER

14%
10% 14%
15%

30% 38%
26%
 r
WEIGHT LOSS IN CANCER

, 2003-4
WEIGHT LOSS IN CANCER
MALNUTRITION AND ITS CONSEQUENCE

• Slow wound healing

• Impaired immunity

• Increase in length of hospital stays

• Increased treatment costs

• Increase in mortality
 LENGTH OF HOSPITAL STAY
Malnutrition increases length and costs of
hospitalization
Nutritional Status

15.6
Severe

10.2
Mild

8.2
Normal

0 5
Days10 15 20

Robinson et al. JPEN 1987

NUTRITIONAL ASSESSMENT

• Simplified form

• Uses validated tool: Subjective

Global Assessment (SGA)

• Incorporates Body Mass Index,

serum albumin, Total
Lymphocyte Count

• Scoring system
 SGA “C” or SEVERE MALNUTRITION
• Weight loss > 10%

• Poor intake for 2 weeks or more

• BMI <18.5

• Subjective Global Assessment – SGA “C”

• Albumin < 3 gm%

• Total lymphocyte count < 1500

NUTRI CARE PLAN

Nutrient
requirements

Pharmaconutrition

Nutrient
formulation

Access & delivery

Monitoring
NUTRIENT MONITOR
 NUTRITION SCREENING
REQUIREMENTS
• Properly calibrated • Adequately trained
instruments: personnel
• Accurate data collection
o Weighing scale
o Stadiometer o Weight and height
• Computer network o Significant weight loss
(≥ 10%)

Correct data = Correct basis of judgment

 ESPEN 2009 GUIDELINES

• Nutritional assessment of all cancer patients should begin

with tumour diagnosis

• Repeat evaluation at every visit to initiate nutritional

intervention early on (Grade C)

ESPEN: European Society of Parenteral and Enteral Nutrition, 2009

APPROACH TO NUTRITIONAL MANAGEMENT
APPROACH TO NUTRITIONAL MANAGEMENT

START OF MANAGEMENT FOR CANCER

• normal • Chemotherapy
• mild malnourished • Radiotherapy
• Combination

START NUTRITION SUPPORT

• Oral
• EN
• Combined EN / PN
• TPN

MONITOR FOR TOLERANCE

 ESPEN 2009 Guidelines

• Total daily energy expenditure in cancer patients is similar in

healthy subjects
o 20-25 kcal/kg/day for bedridden
o 25-30 kcal/kg/day for ambulatory subjects

• The majority of cancer patients requires TPN for only a short

period of time and does not need a special formulation
(Grade C)

ESPEN: European Society of Parenteral and Enteral Nutrition, 2009

NUTRITIONAL REQUIREMENTS COMPUTATION

• Energy intake
o 25-35 kcal/kg/day

• Protein intake
o 1-2 gm/kg/day

• Non-protein calorie
o 50% carbo / 50% fat
o 40% carbo / 60% fat

• Multivitamins and trace elements

ESPEN Guidelines 2009: SURGERY

INDICATION
Preoperative parenteral nutrition is indicated in
severely undernourished patients who cannot be
adequately be fed either by oral or enteral route
(Grade A)
SURGERY IN EARLY STAGE LUNG CANCER
 APPROACH TO NUTRITIONAL MANAGEMENT
PRE-OPERATIVE PHASE
Nutritional Assessment

Normal to moderate Severe Malnutrition • Esophageal resection

malnutrition • Gastrectomy
• Pancreaticoduodenectomy
Enteral nutrition
10-14 days
Immunonutrition
6-7 days

SURGERY

Condition: Patient can eat

 APPROACH TO NUTRITIONAL MANAGEMENT
PRE-OPERATIVE PHASE
Nutritional Assessment

Normal to moderate Severe Malnutrition • Esophageal resection

malnutrition • Gastrectomy
• Pancreaticoduodenectomy

TPN+ Omega-3-Fatty Acids + Antioxidants

(+ glutamine); 6-7 days

SURGERY

Condition: Patient can not tolerate oral intake

APPROACH TO NUTRITIONAL MANAGEMENT
POST-OPERATIVE PHASE
While in the OR ask yourself: “is oral feeding possible within 7 days?”

Yes No

Can I feed within 4 days? Needle catheter jejunostomy

• Enteral nutrition (12 hrs)

Yes No • Better: immunonutrition

“Fast Track” TPN If enteral nutrition is inadequate

Supplemental TPN

Transition
 NUTRITIONAL ASSESSMENT PREDICTS
COMPLICATIONS IN POST CANCER SURGERY
Nutrition risk assessment predicts morbidity and mortality in surgical patients
while in the hospital

Predicting post-operative complications based on surgical nutritional risk level using the SNRAF in colon cancer
patients - a Chinese General Hospital & Medical Center experience. Ocampo R B et al. Phil J Surg Spec 2007;
63(4): 147-53. (Accessible http://www.philspenonline.com.ph/POJ_1.html)
 ESPEN 2009 Guidelines

• Therapeutic goals of TPN in cancer patients are the

improvement in function and outcome by:

o Preventing and treating undernutrition/cachexia

o Enhancing compliance with anti-tumor treatments
o Controlling some adverse effects of antitumor therapies
o Improving quality of life

Grade level C
 PARENTERAL NUTRITION

Total NPO Tube fed Oral - No appetite in

spite of stimulants

PN Unable to reach PN for 1 -2 days

70% of computed 1000 kcal bag
requirements

Usually the 1500 Give parenteral nutrition Once appetite

to 1900 kcal bags intermittently (usually the perks up, shift to
will suffice lower calorie content like oral supplements
1000 kcal bags)

Always add vitamins, trace elements, appropriate electrolytes

 PARENTERAL NUTRITION
Cell membrane receptors and transporters

Nuclear membrane • lipid

• DNA • carbohydrate
• energy production systems
• enzymes • protein
• endoplasmic reticulum
• complex bodies • electrolytes
• Golgi aparatus
• subcellular bodies • trace elements
• tubules • vitamins
• vesicles • glutamine
• Mitochondrial • proteasomes • fish oils
• Transporters • peroxisomes
• membrane enzymes
• energy production systems
The Cell

Why macro + micro? → optimize function / structure

PARENTERAL NUTRITION

Garanowski L. J Intraven Nurs 1993;16:167-194

 PARENTERAL NUTRITION

• Tunneled subclavian catheter

• Implantable infusion port
 ENTERAL FEEDING (PEG)

100
90
80
70
60 2000

number
2001
50
2002
40 2003
30
20
10
0

PEG placement PEG placement,

St Luke’s Medical Center
 NUTRITION SUPPORT : IMPACT ON THE
QUALITY OF LIFE
2
Without PEG
With PEG
1 *p = 0.038
Quality of Life Index
(arbitrary units)

-1 *

Radiation Therapy
-2
0 2 4 6 12 18 24
Weeks

Senft et al. Supp Care Cancer 1993

NUTRITION IMPACT ON BODY COMPOSITION
 NUTRITION SUPPORT IMPACT ON THE
IMMUNE SYSTEM
Immune effects of 10 day TPN,
oncosurgical patients
250 237

200 174
IgM mg/dL

150

100

50

0
pre_rx day10

Natural killer cell activity restored to normal, Bozzetti, 1995

“In all maladies, those who
are well nourished do best”
Hippocrates, 400 BC
THANK YOU!